June 20, 2011

HCV Treaters Shortage Editorial - Distributive justice and the arrival of direct-acting antivirals: Who should be first in line?

"The availability of DAA therapy will forever change the landscape of HCV, in that we will be able to cure patients of disease who we were unable to cure in the past. Unfortunately, this medical breakthrough will be coupled with resource scarcity. Historically, some of the greatest scientific discoveries in medicine have failed to provide a distribution system that appropriately emphasized not only justice and equality but also medical need. We hope to learn from the past by proposing a preconceived plan that would both educate patients and allocate therapy to the neediest patients first, thereby fulfilling the moral framework of distributive justice."

"On average, a health care provider can reasonably initiate therapy on only three patients each week before exceeding their work capacity.....current staffing will be unable to meet the demands of all patients with HCV who are expected to request treatment......We propose a needs-based allocation system....patients who have previously deferred therapy and new patients will be prioritized on the basis of need, with patients with cirrhosis at one end of the spectrum and asymptomatic patients with F0-F2 fibrosis at the other end of the spectrum. This system satisfies the principle of justice while placing appropriate emphasis on medical need."

Volume 53, Issue 6, pages 1789Ð1791, June 2011

Andrew Aronsohn M.D.,à, Donald Jensen M.D.

Center for Liver Disease, Section of Gastroenterology, Hepatology and Nutrition, 5841 South Maryland Avenue, MC 7120, Chicago, IL 60637.

In recent years, each edition of HEPATOLOGY has included a viewpoint article written by a member of the Editorial team. This month Dr Michael Charlton has offered his turn at the microphone to Dr. Donald Jensen and Dr Andrew Aronsohn from the University of Chicago, in order that they can address a pressing issue that will emerge in tandem with the likely approval by the U.S. Food and Drug Administration of boceprevir and/or telaprevir.

More than 120 million people are infected with hepatitis C worldwide.1 Hepatitis C virus (HCV) is a leading cause of liver-related mortality and is the most common indication for liver transplantation in the United States.2 Since the introduction of pegylated interferon and ribavirin nearly 10 years ago, response rates have been relatively stagnant, with less than half of treated patients achieving a sustained virological response.2 Data from the first direct-acting antiviral (DAA) agent, BILN 2061, was initially presented at the American Association for the Study of Liver Diseases annual meeting in 2002, which sparked enthusiasm over improving therapeutic efficacy.3 Nearly a decade later, we find ourselves on the brink of a new era of HCV therapy. Telaprevir and boceprevir will likely receive U.S. Food and Drug Administration approval by mid-2011(they both recd FDA approval a few weeks ago), and based on phase 2 and 3 data, will significantly improve rates of sustained virological response in patients infected with HCV genotype 1 when compared to current standard-of-care therapy.4-7 This improved efficacy has been well-publicized for years, and anticipation of DAA availability has already become part of the HCV treatment algorithm. Greater understanding of the natural history of HCV and identification of risk factors for progression to advanced liver disease has allowed many physicians to recommend deferral of standard-of-care therapy in favor of waiting for DAA availability for patients who are at low risk to progress to significant liver disease in the near future. This was demonstrated in a large VA-based study of 4084 patients evaluated for HCV therapy with interferon and ribavirin.8 Of the eligible patients who declined therapy, 50.3% stated they had deferred treatment in anticipation of more effective medications.8 Treatment-naive patients who have deferred standard-of-care therapy, in addition to patients who have failed previous regimens of HCV treatment, will likely create a surge of requests to initiate therapy in mid-2011.

The influx of patients requesting HCV therapy will present a significant problem. HCV therapy is becoming increasingly complex, and the addition of DAAs will only add to the time needed to effectively educate and appropriately monitor patients while they are receiving treatment. This may be partially offset by response-guided therapy that shortens treatment duration. We recently performed a time analysis study at our institution to gain understanding of time allotment needed for each new DAA-treated patient and to estimate the maximum patient capacity of a health care provider. On average, a health care provider can reasonably initiate therapy on only three patients each week before exceeding their work capacity. Because we anticipate at least 500 requests for evaluation for HCV therapy within the first few weeks of DAA availability, current staffing will be unable to meet the demands of all patients with HCV who are expected to request treatment.

Resource scarcity will be a prominent issue once DAA therapy becomes available. Historically, enthusiasm over a scientific breakthrough has caused the medical community to lose sight of the importance of prediction and resolution of problems of scarcity.9 In 1922, Frederick Banting and Charles Best discovered how to produce and use insulin to treat diabetes mellitus. Word of this life-saving medication traveled quickly, creating a deluge of requests for insulin that could not possibly be fulfilled due to limitations of production capacity.10 Unprepared to handle this dilemma, Dr. Banting created a somewhat arbitrary and subjective plan where Banting himself decided whom to treat first, which resulted in friends and politically well-connected individuals unfairly receiving priority over others.9 Twenty years later, penicillin was discovered, and efforts were made to avoid the injustices seen with insulin allocation. From 1942 to 1944, the Committee on Chemotherapeutic and Other Agents was responsible for rationing penicillin to civilians.11 Although efforts were made to prioritize clinical need over political and social worth, penicillin allocation became subject to intense scrutiny due to a double standard in rationing for civilian and military personnel. Penicillin was carefully allocated to civilians based on severity of disease; however, it was liberally given to military personnel to treat gonorrhea, a less serious illness, because it was highly effective and allowed soldiers to quickly return to their duties.9 In 1960, Belding Scribner developed a shunt that allowed patients with chronic kidney disease to safely undergo dialysis.12 Given the paucity of dialysis machines compared to the number of patients with chronic kidney disease, physicians were once again forced to allocate scarce, life-saving technology. A nine-member committee consisting of two physicians and seven lay persons was formed in 1961 to determine who would receive dialysis services. Because most patients with chronic kidney disease had similar medical needs for dialysis, the committee made decisions in part based on a patient's Òsocial worth.Ó9 Not surprisingly, this criterion was widely criticized and eventually led to approval of legislation in 1972 to allow federal funding for hemodialysis to all Americans with chronic kidney disease.

In 2011, nearly a century after the discovery of insulin, we continue to struggle with issues of resource scarcity. Equitable distribution of antiretroviral medication to patients with human immunodeficiency virus worldwide and organ allocation for transplantation illustrate that despite major advances in medical technology, our underlying moral dilemmas remain unchanged. History has taught us that failure to preemptively develop a moral framework to deal with problems of scarcity can lead to injustices to patients in need. Distributive justice is a moral principle that emphasizes Òfair, equitable, and appropriate distributionÓ of scarce resources.13 Equality for all patients should be paramount, yet this should be carefully balanced with appropriate emphasis on medical need. With the arrival of DAA therapy, we will be unable to initially treat all patients requesting therapy, and we will once again be forced to allocate a scarce resource. Critical analysis of this problem has yielded two potential solutions for this allocation dilemma: a first-come, first-served approach and a needs-based approach.

A conventional first-come, first-served approach, as the name implies, offers therapy, when appropriate, to patients in the order in which they are seen in the clinic after DAA launch. If (and when) the health care team becomes saturated, a waiting list will form, and patients on that list will be offered therapy when the health care team has more capacity. This approach has some advantages. It is the simplest plan and requires no planning prior to DAA availability. In fact, this approach will likely be a default system used by any center that has not enacted a preconceived DAA allocation system. First-come, first-served strictly adheres to the principle of justice, because all patients have an equal claim to therapy, and specific prioritizations are not made. However, it is inadequate because it ignores the importance of medical need where the workforce available to treat is limited in relation to the need.

We propose a needs-based allocation system. Much like the Model for End-Stage Liver Disease system, priority would be given to the sickest patients first in an effort to optimize outcomes for all patients with HCV. Prior to the launch of DAA therapy, treatment-eligible patients with HCV could be provided with an educational symposium outlining the natural progression of HCV and describing an allocation system, which would stress the importance of expediting treatment for the sickest patients and the safety of waiting for therapy in patients with early stages of disease. Then, patients who have previously deferred therapy and new patients will be prioritized on the basis of need, with patients with cirrhosis at one end of the spectrum and asymptomatic patients with F0-F2 fibrosis at the other end of the spectrum. This system satisfies the principle of justice while placing appropriate emphasis on medical need.

There will be inherent difficulties in this prioritization system. First, many patients with early stage disease have been eagerly awaiting the launch of DAA therapy and may be disappointed to find out that they may have to wait even longer to initiate therapy. Although it is anticipated that educational sessions will help these patients understand the reasoning behind their increased wait time, some patients will still choose not to wait and will seek more expedited treatment elsewhere. In addition, the choice to treat patients with more advanced liver disease first will likely result in poorer initial outcomes and more complications related to therapy. Finally, there may be medical legal implications to treating patients who are outside of approved indications for therapy. However, the benefit of a morally sound allocation system should outweigh these legal risks, and by ensuring that health care providers have adequate time with each patient, adverse outcomes can be greatly diminished.

The availability of DAA therapy will forever change the landscape of HCV, in that we will be able to cure patients of disease who we were unable to cure in the past. Unfortunately, this medical breakthrough will be coupled with resource scarcity. Historically, some of the greatest scientific discoveries in medicine have failed to provide a distribution system that appropriately emphasized not only justice and equality but also medical need. We hope to learn from the past by proposing a preconceived plan that would both educate patients and allocate therapy to the neediest patients first, thereby fulfilling the moral framework of distributive justice.


# 1Shepard CW, Finelli L, Alter MJ. Global epidemiology of hepatitis C virus infection. Lancet Infect Dis 2005; 5: 558-567.

# 2Strader DB, Wright T, Thomas DL, Seeff LB; American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C. HEPATOLOGY 2004; 39: 1147-1171.

# 3Hinrichsen H. First report on the antiviral efficacy of BILN 2061, a novel oral serine protease inhibitor, in patients with chronic hepatitis C genotype 1 [Abstract]. HEPATOLOGY 2002; 36:Abstract 866.

# 4Poordad F, McCone J, Bacon BR, Bruno S, Manns MP, Sulkowski MS, et al. Boceprevir (BOC) combined with peginterferon alfa-2b/ribavirin (P/R) for treatment-na•ve patients with hepatitis C virus (HCV) genotype (G) 1: SPRINT-2 final results [Abstract]. HEPATOLOGY 2010; 52( 4 Suppl.): 402A-403A.

# 5Kwo PY, Lawitz EJ, McCone J, Schiff ER, Vierling JM, Pound D, Davis MN, et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet; 376: 705-716.

# 6McHutchison JG, Everson GT, Gordon SC, Jacobson IM, Sulkowski M, Kauffman R, McNair L, et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med 2009; 360: 1827-1838.

# 7Sherman KE, Flamm SL, Afdhal NH, Nelson DR, Sulkowski MS, Everson GT, et al. Telaprevir in combination with peginterferon alfa2a and ribavirin for 24 or 48 weeks in treatment-na•ve genotype 1 HCV patients who achieved an extended rapid viral response: Final results of phase 3 ILLUMINATE study [Abstract]. HEPATOLOGY 2010; 52( 4 Suppl.): 401A-402A.

# 8Bini EJ, Brau N, Currie S, Shen H, Anand BS, Hu KQ, Jeffers L, et al. Prospective multicenter study of eligibility for antiviral therapy among 4,084 U.S. veterans with chronic hepatitis C virus infection. Am J Gastroenterol 2005;100:1772-1779.

# 9McGough LJ, Reynolds SJ, Quinn TC, Zenilman JM. Which patients first? Setting priorities for antiretroviral therapy where resources are limited. Am J Public Health 2005; 95: 1173-1180.

# 10Shampo MA, Kyle RA. Frederick bantingÐNobel laureate for discovery of insulin. Mayo Clin Proc 2005; 80: 576.

# 11Adams DP. Wartime bureaucracy and penicillin allocation: the Committee on Chemotherapeutic and Other Agents, 1942Ð44. J Hist Med Allied Sci 1989; 44: 196-217.

# 12Blagg CR. The early history of dialysis for chronic renal failure in the United States: a view from Seattle. Am J Kidney Dis 2007; 49: 482-496.

# 13Beauchamp TL, Childress JF. Principles of Biomedical Ethics. 5th ed. New York, NY: Oxford University Press; 2001.

Boceprevir & Peginterferon Patient Assistance Programs

1 866 939 HEPC (4372)



Telaprevir Patient Assistance Program

Helping People with Hepatitis C Get INCIVEK

The people who work at Vertex understand that medicines can only help patients who can get them. With that in mind, the company today introduced a comprehensive financial assistance and patient support program to help people get INCIVEK who might not otherwise be able to afford it. The program will help people with hepatitis C learn about insurance benefits for their medicines, give INCIVEK for free to eligible patients who do not have insurance and provide coverage for co-pay or co-insurance costs associated with INCIVEK for people who meet certain program criteria. Additionally, patients will have access to nurses through a 24-7 hotline by which they can receive support, guidance and educational materials about hepatitis C and its treatment. Vertex will also provide nurses and doctors with educational tools and resources so they can offer support and care to people with hepatitis C before, during and after the treatment process.

For eligible patients, the program includes the following:

· Insurance Benefits Research and Support: Vertex case managers will research patients' insurance benefits for INCIVEK combination treatment, assist people with insurance appeals and help guide them to other forms of financial support, including Vertex's free medicine and co-pay programs;

· Free Medicine Program: Vertex will give INCIVEK for free to people who do not have insurance and have an annual household income of $100,000 or less; and

· Co-Pay Support: Vertex will cover co-pay or co-insurance costs up to 20 percent of the total cost of INCIVEK for people who have private insurance plans that cover INCIVEK, regardless of their household income. For people covered by government insurance, Vertex will also make donations to the independent, non-profit Patient Access Network Foundation, which has a fund to provide co-pay support to people taking hepatitis C medicines.

More information about this program is available by calling 1-855-837-8394 or visiting http://www.incivek.com/.

Vertex Telaprevir Hep C Care Website:

Speak to a Nurse
Call 1-888-552-2494 to speak with a nurse about hepatitis C testing and treatment.


Activists Call for Earlier Access to Hep C Treatments

June 16, 2011

Hepatitis and HIV activists have called for pharmaceutical companies and drug regulators to provide earlier access to new hepatitis C virus (HCV) therapies in development to people at greater need of treatment, including people on transplant wait lists and those coinfected with HCV and HIV. These demands were issued following a meeting of 50 activists, researchers, regulators and pharmaceutical representatives held in early June in Sitges, Spain.

The recent approval of Incivek (telaprevir) and Victrelis (boceprevir) has ushered in a new era of treatment for people with HCV. Whereas people infected with the hard-to-treat strains of HCV (genotypes 1 and 4) had previously achieved cures about half the time, the addition of these new drugs to standard HCV therapy has increased cure rates by up to 50 percent and shortened the duration treatment for many.

The future also looks bright, with several drugs active against HCV in the pipeline, several of which are currently in Phase II studies. Unfortunately, however, companies have been relatively slow to provide early access to new treatments—such as compassionate use programs providing drug to those who don’t qualify for clinical trials—for those who desperately need novel therapies, such as those with advanced cirrhosis and those undergoing liver transplants. Researching the drugs in people with these conditions and in people coinfected with HIV and HCV has also been slow, according to activists.

For several years now, key stakeholders have been meeting in Sitges each year to discuss issues that hindered the development of and access to new HCV therapies for people in greatest need of more options. At this year’s meeting, early access to new treatments was at the top of the agenda.

“Meeting participants emphasized the need for early access for ‘difficult-to-treat’ populations, including patients with HIV/HCV coinfection or liver cirrhosis, people who have undergone liver transplantation or are currently on transplant waiting lists, people in marginalized groups such as drug users, and particularly, access to interferon-free regimens for people who need them,” explained representatives from one of the meeting’s key sponsors—the European Community Advisory Board (ECAB).

“The most urgent need,” the group continued, “is for people with advanced disease who have no other treatment options and cannot wait for full approval of new therapies.”

Though there was agreement at the meeting about the need to move more quickly in these populations, activists insisted that more effort is needed by companies to conduct studies sooner in the drug development process so that people in greatest need may gain earlier access to the drugs.

“It is critical to study pharmacokinetics, safety and efficacy in a wide-range of groups that will use these drugs in real world practice,” stated ECAB. “New [direct acting hepatitis drugs] must be evaluated for drug-drug interactions with HIV antiretroviral agents, opiate substitution therapy (methadone and buprenorphine), immunosuppressants, antidepressants and other medications commonly used by people with hepatitis C.”

ECAB also insisted that researchers and companies share data about these kinds of drug interactions early and to involve activists in decision making and safety monitoring throughout.

New Diagnostic Algorithm for Hepatic Lesions Introduced

Gastroenterology & Endoscopy News
ISSUE: JUNE 2011 | VOLUME: 62:06

by Caroline Helwick

San Francisco—Morris Sherman, MD, PhD, associate professor of medicine at the University of Toronto, spoke about diagnostic imaging for hepatocellular carcinoma (HCC) at the 2011 American Society of Clinical Oncology Gastrointestinal Cancers Symposium.

“Instead of requiring two more or less consecutive contrast radiographic studies to define if a lesion is positive for cancer or not, one image is now considered acceptable if the findings are typical,” he said, referring to the new American Association for the Study of Liver Disease (AASLD) guidelines on HCC. “If one study’s findings are not typical but the second study’s are, that is also good enough. This cuts down on the total number of radiographic studies required, and also reduces the number of biopsies that are needed.”

The rationale for the updated AASLD guidelines largely pertains to small lesions. More than half of nodules less than 1 cm are not HCC. Biopsy of small lesions is difficult and unreliable, and the appearance of small HCC lesions is rarely typical. “Putting a needle accurately into a very small lesion is a big problem,” Dr. Sherman said. “The false-positive rate is very high, hence the recommendation is to watch these lesions.”

New Diagnostic Algorithm

In the new diagnostic algorithm put forth in the AASLD guidelines, a nodule identified by ultrasound is stratified based on size and treated accordingly. For lesions less than 1 cm, the AASLD recommends a repeat ultrasound in three months followed by surveillance. If the lesion grows or changes in character, further investigation is warranted. For lesions greater than 1 cm, additional work-up is necessary, including a four-phase multidetector computed tomographic (CT) scan or dynamic contrast-enhanced magnetic resonance imaging (MRI) test. Lesions with arterial hypervascularity and venous and delayed-phase washout are considered positive for HCC. If negative for these features (i.e., the appearance is atypical), the other contrast-enhanced study (i.e., MRI or CT) should be performed. If those results also are negative, the lesion should be biopsied, the guidelines state.

This strategy minimizes resource utilization. If the first scan does not show typical features of HCC, then a second contrast-enhanced study is performed. This increases the sensitivity, with little loss of specificity, and reduces the frequency of biopsies, Dr. Sherman explained.

However, “if the objective is to maximize accuracy and never treat incorrectly, then two contrast-enhanced studies should be done, as per the older guidelines.” But this strategy results in a significant number of biopsies, Dr. Sherman noted.

Important Caveats

“These changes are reflected in the new guidelines, but there are several important principles to keep in mind,” Dr. Sherman said.

First, the radiographic features of HCC, when present, are highly specific. The lesion is more enhanced than the surrounding liver in the arterial phase and less enhanced than the surrounding liver in the venous phase of the examination. When these features are not present, a biopsy is required, he said. Second, the new guidelines apply only to situations when HCC is likely to be identified, as in patients known to be at risk. In patients with a liver mass and no underlying liver disease, the algorithm does not apply and the approach is different. If the lesion is likely to be malignant or otherwise requires resection, biopsy is not indicated because the diagnosis will be confirmed from the surgical specimen.

Hashem B. El-Serag, MD, MPH, chief of gastroenterology and hepatology at Baylor College of Medicine, in Houston, said, “the new guidelines bring an enlightened interpretation of the existing literature on HCC diagnosis. However, the evidence base from which these guidelines stem is mostly retrospective data and nonrandomized clinical trials. Furthermore, the utility of the diagnostic guideline has not been tested. Local resources and expertise should be considered when applying the guidelines, in particular, the ability to exclude HCC based on cross-sectional imaging studies.”


Also See: AASLD Publishes New Guideline on HCC

Dramatic Reduction in HCV Morbidity, Mortality Could Be Gained With Targeted Screening of Baby Boomers

Gastroenterology & Endoscopy News
ISSUE: JUNE 2011 | VOLUME: 62:06

by David Wild

Chicago—Researchers are calling for a targeted hepatitis C virus (HCV) screening campaign for all baby boomers. They believe that doing so will significantly cut the burden of HCV-related advanced liver diseases and cancers.

The investigators, who presented estimates of the impacts of such an approach at the 2011 Digestive Disease Week meeting (abstract 477), argued that existing risk-based screening fails to capture people who may have contracted HCV decades ago and are potential carriers of dormant disease, but who do not currently engage in high-risk activity.

A blanket age-based screening protocol among those born between 1945 and 1970 would capture many of these patients, said Anna Lok, MD, who was not involved in the study.

“Screening by birth cohort identifies an age group at the greatest risk for HCV, simplifying the process of screening selection and avoiding the potential issues of patients denying risk factors or physicians forgetting to inquire about risk factors,” said Dr. Lok, director of clinical hepatology and professor in the Department of Internal Medicine, University of Michigan Health Center, Ann Arbor.

Study investigator Lisa McGarry, MPH, director of health economics and outcomes research at Innovus, a branch of Ingenix Life Sciences (Medford, Mass.), said her research team used existing HCV prevalence rates to create a Markov probability model estimating the rates of HCV infection and infection-related liver disease in the baby boomer generation. The model included variables such as rates of spontaneous viral clearance, disease progression, treatment response and state-specific mortality to help predict rates of cures, progressive disease and carcinomas.

Ms. McGarry and her colleagues assumed screening by age group would capture all of the estimated 1.6 million HCV-infected baby boomers in the country if implemented over a five-year period, while a risk-based approach would screen less than 3% of infected individuals (Shatin D et al. Am J Manag Care 2004;10:250-256). Given these assumptions, they estimated an age-based HCV screening approach would reduce the incidence of advanced liver disease in this population by 106,000 cases and related hepatocellular carcinomas by approximately 35,000 cases. Overall, screening by age would result in 7,000 fewer HCV-related liver transplants and 59,000 fewer HCV-related deaths over the generation’s life span.

This five-year screening campaign, however, would cost $45.1 billion, substantially more than the $32 billion that the current risk-based screening program costs. Age-based screening would extend lives at a relatively low cost of $25,279 per quality-adjusted life-year gained.

Co-investigator Zobair M. Younossi MD, MPH, said that treatment outcomes with an age-based HCV screening approach will further improve as newer classes of HCV drugs are introduced in the clinical setting.

“In this particular age group, this is a cost-effective approach to extending HCV infected individuals’ life spans and improving their quality of life,” said Dr. Younossi, vice president for research at Inova Health System, and executive director at the Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, Va.


AASLD Publishes New Guideline on HCC

Gastroenterology & Endoscopy News
ISSUE: JUNE 2011 | VOLUME: 62:06

by Christina Frangou

The American Association for the Study of Liver Diseases (AASLD) has issued a new practice guideline on the management of hepatocellular carcinoma (HCC), after recent data made a 2005 version obsolete. The authors called for greater surveillance of high-risk groups as well as changes to diagnostic, surveillance and staging techniques, including dropping alpha-fetoprotein (AFP) from the list of recommended tests and adding sorafenib to the list of acceptable treatments.

“In the past decade, [HCC] has gone from being an almost universal death sentence to a cancer that can be prevented if detected at an early stage and effectively treated,” wrote the authors of the guideline, which was published in the March 2011 issue of the journal Hepatology (Bruix J et al. Hepatology 53:1020-1022).

Gastroenterologist Lewis R. Roberts, MB, ChB, PhD, called the document a “very important” aid for clinicians. “There were no major surprises in the guideline,” said Dr. Roberts, professor of medicine at Mayo Clinic in Rochester, Minn. “It reflects the preponderance of evidence for screening diagnosis and therapy for HCC. And it recognizes our change in viewpoint that HCC has become a cancer that can be detected at an early stage and effectively treated or transformed into a chronic disease.”

AFP Testing

In a letter to Hepatology, Jorge A. Marrero, MD, associate professor of internal medicine at the University of Michigan, Ann Arbor, and Hashem B. El-Serag, MD, professor of medicine at Baylor College of Medicine, Houston, criticized the omission of AFP, saying the guidelines “ignore a significant amount of data” about its efficacy in surveillance of patients at risk of HCC (2011;53:1060-1061). “In the absence of randomized studies in patients with cirrhosis, the current evidence points to US [ultrasonography] combined with serum AFP as the most effective surveillance strategy for patients at risk for HCC. The guidelines should be revised to recommend US with AFP as the best-available surveillance strategy,” they wrote.

The guideline authors responded, saying they stand by their recommendation of surveillance by US every six months.

“Although the randomized controlled study of HCC screening used both AFP and US, we believe that contribution of AFP to the outcome was minimal and maintain our position that it should not be used. US is a better test, and we should not be recommending inferior tests in guidelines such as this,” they said.

Screening and Surveillance

Much of the guidelines focus on improving surveillance for HCC. Surveillance is considered cost effective if the expected risks exceed 1.5% per year in patients with hepatitis C and 0.2% in patients with hepatitis B. Screening is recommended every six months for Asian male hepatitis B carriers over age 40; Asian female hepatitis B carriers over age 50; hepatitis B carriers with a family history of HCC; African/North American blacks with hepatitis B; cirrhotic hepatitis B carriers; and patients with hepatitis C cirrhosis, stage 4 primary biliary cirrhosis, genetic hemochromatosis and cirrhosis, alpha-1 antitrypsin deficiency and cirrhosis.

Diagnosis should be based on imaging techniques and/or biopsy. Staining for glypican 3, heat shock protein 70 and glutamine synthetase can help reinforce expert pathology diagnoses. Positive results on two of the three stains confirm HCC. The authors do not recommend contract-enhanced US, saying it may offer false-positive HCC diagnosis in patients with cholangiocarcinoma. Moreover, they recommend diagnostic imaging criteria be applied only to patients with cirrhosis of any etiology and patients with chronic hepatitis B who may not have fully developed cirrhosis or regressed cirrhosis.

The standard for staging has changed as well. The authors said that the Barcelona-Clinic Liver Cancer staging system has become the “de facto system that is used.”

Treatment Options

Sorafenib, the first approved targeted agent for the treatment of HCC, is now considered the “first-line treatment” in patients with HCC who can no longer be treated with potentially more effective therapies.

“These patients did not have any effective option until now and the availability of a treatment option represents a major advancement,” said Dr. Bruix.


Novel Pegylated Interferon Safer, More Effective Than Current Treatment, Study Shows

Gastroenterology and Endoscopy News
ISSUE: JUNE 2011 | VOLUME: 62:06

by David Wild

Berlin—A novel variant of pegylated interferon (PegIFN) called PegIFN-lambda is significantly more effective than PegIFN-alfa-2a (Pegasys, Genentech) at suppressing viral loads in patients with certain genotypes of hepatitis C virus (HCV), according to preliminary findings from an ongoing randomized trial. Patients also experienced fewer adverse events on the novel PegIFN.

“If the superior virological response rates and minimal adverse events are sustained through the completion of this study and replicated in other research, this form of interferon will represent a major advance in the treatment of chronic hepatitis C,” said Emmet Keeffe, MD, professor emeritus of medicine, Stanford University Medical Center, Palo Alto, Calif., who was not involved in the study.

An estimated 20% of patients stop treatment for HCV because of side effects associated with PegIFN-alfa-2a. PegIFN-lambda attaches to fewer cellular receptors than PegIFN-alpha-2a and thus may be a safer and equally effective alternative.

In this study, lead researcher Stefan Zeuzem, MD, and colleagues at 39 international centers randomly assigned individuals with chronic HCV to receive ribavirin in combination with PegIFN-alfa-2a 180 mcg (n=132), PegIFN-lambda 120 mcg (n=130), PegIFN-lambda 180 mcg (n=131) or PegIFN-lambda 240 mcg (n=133). The study is ongoing, but the current efficacy and safety findings are based on 12 weeks of double-blinded treatment.

The data showed that 14.7% and 16.5% of those with HCV genotypes 1 and 4 who received 180 and 240 mcg of PegIFN-lambda, respectively, experienced a rapid virologic response (RVR) to the novel drug compared with 5.8% of patients with the same HCV genotypes who took PegIFN-alfa-2a (P<0.05). The RVR rate among individuals with genotypes 1 and 4 who received 120 mcg of PegIFN-lambda was 6%.

Complete early virologic response rates were 55%, 55.9% and 56.3% among those with HCV genotypes 1 and 4 who received 120, 180 and 240 mcg of PegIFN-lambda compared with 37.9% among PegIFN-alfa-2a recipients (P<0.05). Response rates among those with HCV genotypes 2 and 3 did not differ significantly between the treatment groups, the researchers reported.

Patients administered PegIFN-lambda also experienced fewer flu-like and musculoskeletal symptoms as well as fewer cytopenias (Table). However, aspartate and alanine transaminase levels rose to more than five times the upper limit of normal in 17.4% of those receiving the highest dose of PegIFN-lambda, and direct bilirubin concentration exceeded 1.2 mg/dL in 7.6% of patients in the same group. These adverse events resolved with dose reduction or drug discontinuation.

Table. Adverse Events in Patients Receiving PegIFN-lambdaa For Hepatitis C Virus Infection
PegIFN-alfa-2a 180 mcg (n=132)PegIFN-lambda 240 mcg (n=133)PegIFN-lambda 180 mcg (n=131)PegIFN-lambda 120 mcg (n=130)
Flu-like symptoms42.9%9.7%9.9%12.5%
Musculoskeletal symptoms46.6%14.2%14.5%18%
Hemoglobin <10 g/dL44%12.9%15.4%20.5%
Neutrophils <750/mm315.2%0.8%
Platelets <50,000/mm314.4%
PegIFN, pegylated interferon a All patients also received ribavirin.

“This is indeed a promising new drug,” said Dr. Zeuzem, professor and chair, Department of Medicine, Johann-Wolfgang Goethe University Hospital, Frankfurt/Main, Germany, who presented his group’s findings at the 46th annual meeting of the European Association for the Study of the Liver (Abstract 1360).

“Now we need to assess longer-term sustained virological responses and to accumulate more safety data,” he said.


Statin Appears To Boost Efficacy of Pegylated Interferon-Ribavirin for Treatment of Hepatitis C

Gastroenterology and Endoscopy News
ISSUE: JUNE 2011 | VOLUME: 62:06

by David Wild

Berlin—A new study found that adding 20 mg daily of fluvastatin to pegylated interferon-ribavirin (PegIFN-ribavirin) significantly increased the likelihood that patients with chronic hepatitis C virus (HCV) infection will have early and sustained virologic responses. The findings add to a growing body of evidence that shows statins have an important place in the treatment of chronic HCV infection.

“These data, as well as preliminary findings from an ongoing trial I am helping conduct, support the addition of fluvastatin to peginterferon and ribavirin for treating some hepatitis C patients,” commented Ted Bader, MD, director of liver diseases at the University of Oklahoma Health Sciences Center, in Norman, who was not involved in the current study.

Since a study that was published in 2008 showed fluvastatin monotherapy reduced HCV loads in 31 infected patients, interest in the potential use of the drug for this indication has increased (Bader T et al. Am J Gastroenterol 2008;103:1383-1389).

To further explore the drug’s use in treating HCV, Eugen Georgescu, MD, PhD, and colleagues compared viral loads and liver function between 104 patients with HCV who were randomly assigned to receive PegIFN-ribavirin plus fluvastatin 20 mg once daily and 105 patients with HCV given PegIFN-ribavirin plus a placebo, both for 48 weeks. None of the subjects had used statin medications within the year before study onset and all were followed for 24 weeks. Fifty subjects had metabolic syndrome.

Dr. Georgescu, who presented the findings at the 46th annual meeting of the European Association for the Study of the Liver (abstract 2922), said that viral loads at study onset were similar in both groups: 3.79±0.29 106 IU/mL for placebo versus 3.47±0.26 106 IU/mL for the fluvastatin group. After 12 weeks of treatment, mean HCV loads decreased to 0.33±0.04 106 IU/mL in the placebo group and 0.21±0.03 106 IU/mL in the fluvastatin group. The reduction in viral loads was significantly greater in the treatment group (94.53%) than in the placebo group (91.74%) compared with baseline (P=0.031).

Moreover, 76% of statin recipients experienced an early virologic response after 12 weeks of treatment, in contrast to 62% of patients in the placebo group (P=0.049). Viral suppression persisted at 72 weeks in significantly more patients who received fluvastatin compared with placebo recipients (63% vs. 50%, respectively; P=0.05).

The added efficacy of fluvastatin held regardless of metabolic syndrome status; 85% of fluvastatin and 71% of placebo recipients without metabolic syndrome had an early virologic response, and 74% and 58% of the same groups showed a sustained response at 72 weeks (P<0.05 for both).

The researchers said that although fluvastatin use resulted in statistically significant improvements, the changes were relatively modest.

“Nevertheless, our results justify further research to confirm statins as an adjuvant therapy in chronic hepatitis C and to understand the mechanisms underlying its synergistic effects with PegIFN-ribavirin therapy,” concluded Dr. Georgescu, professor in the Department of Internal Medicine/Gastroenterology, Filantropia Municipal Hospital, in Craiova, Romania.


Hepatitis C Treatment Changing Rapidly With Approvals Of Two New Drugs

Gastroenterology & Endoscopy News
ISSUE: JUNE 2011 | VOLUME: 62:06

by Rosemary Frei

On the heels of data presented at the 46th annual meeting of the European Association for the Study of the Liver (EASL) meeting and this year’s Digestive Disease Week meeting came the FDA approval of two new drugs designed to boost the effectiveness of peginterferon-ribavirin therapy for patients with chronic hepatitis C virus (HCV) genotype 1 infection. On May 13, the FDA approved boceprevir (Victrelis, Merck) followed days later by the approval of telaprevir (Incivek, Vertex/Tibotec), marking an eagerly anticipated revolution in the management of patients with HCV.

Cascade of Data

Data on the new drugs have not been in short supply. An article published last year in The New England Journal of Medicine on the use of telaprevir for previously treated patients with chronic HCV genotype 1 infection brought this new class of agents—inhibitors of HCV protease—into the spotlight (McHutchison JG et al. 2010;362:1292-1303). The results of the randomized, double-blind phase II study—known as PROVE3 (Protease Inhibition for Viral Evaluation 3)—indicated that the addition of telaprevir for as few as 12 weeks significantly increased sustained virologic response (SVR).

Two Phase III studies published in March indicated that boceprevir also boosted efficacy in as few as 24 weeks. Results of the RESPOND-2 (Retreatment with HCV Serine Protease Inhibitor Boceprevir and Peginterferon/Rebetol 2) trial indicated that the three-drug cocktail nearly tripled SVR rates in previously treated patients (Bacon BR et al. N Engl J Med 2011;364:1207-1217). Furthermore, data from the SPRINT-2 (Serine Protease Inhibitor Therapy 2) trial also showed that SVR rates in treatment-naïve patients are boosted significantly with the addition of boceprevir (Poordad F et al. N Engl J Med 2011;364:1195-1206).

Final results from the Phase III REALIZE (Re-treatment of Patients with Telaprevir-based Regimen to Optimize Outcomes) trial also were presented at the EASL meeting. These data included all three major subgroups of patients who were not cured with a prior course of interferon-based therapy, including null responders.

All of the boceprevir studies were paid for by Merck, and the telaprevir studies were sponsored by Vertex and its collaborator, Tibotec.

Stephen H. Caldwell, MD, professor of medicine and director of hepatology, University of Virginia Health System, Charlottesville, pointed out that the emerging therapies for hepatitis C offer a significant increase in sustained viral eradication but also bring treatment complexity, side effects and expense.

“Emerging from the myriad of study names are new monitoring recommendations and prognostic indicators that will take time to really understand,” Dr. Caldwell said. “We should recall that the best-performed studies are closely monitored, often at a level unachievable in clinical practice. Clearly, the field has changed rapidly in a very short period of time. Careful assessment and thoughtful consideration will be key to optimizing success and minimizing failure,” he said.

Boceprevir Trials

In a poster presented at the EASL meeting, John M. Vierling, MD, and colleagues from Baylor College of Medicine in Houston analyzed the relationship between patients’ response during the lead-in period in the boceprevir trials and overall SVR rates. The investigators defined response during the lead-in period as at least a 1.0-log10 reduction in HCV RNA. Data from the SPRINT-2 and RESPOND-2 trials were combined for this study.

The researchers found a steady, stepwise increase in the percentage of patients achieving SVR after at least 24 weeks of triple-agent therapy based on the level of decrease in viral load after the four-week lead-in period with peginterferon-ribavirin alone. The pattern was particularly noticeable among non-black patients. Overall, the advantage of adding boceprevir was greatest for patients with less responsiveness to interferon.

“Patients in the boceprevir arms with a poor response to interferon had sufficiently high rates of SVR as compared with the control group. … [This] dispels concern that the addition of boceprevir to the treatment regimen would be the equivalent of functional monotherapy,” the investigators noted. “However, patients who have a poor response to the interferon may need to be monitored closely to determine who may benefit from better therapies, once they are available.”

They add that conversely, addition of boceprevir may not boost SVR rates among patients with undetectable HCV RNA levels after the lead-in period, but that “in the majority of these patients, total treatment duration is shortened to 28 weeks.”

The four most common treatment-related adverse events (AEs) in the RESPOND-2 and SPRINT-2 studies were fatigue, headache, nausea and anemia. In RESPOND-2, treatment discontinuation due to anemia occurred in 3% of boceprevir patients in 48-week treatment only. None of the controls discontinued due to anemia. The respective numbers for SPRINT-2 were 2%, 2% and 1%.

Erythropoietin was allowed for the treatment of anemia at the discretion of the investigators, and in RESPOND-2 was used by 41% and 46% of boceprevir patients in the response-guided and 48-week treatment arms, respectively, compared with 21% of patients in the control arm. In SPRINT-2, the respective numbers were 43%, 43% and 24%. (P values were not supplied.)

Fred Poordad, MD, chief of hepatology and liver transplantation at the Comprehensive Transplant Center at Cedars-Sinai Medical Center in Los Angeles, and lead investigator of the SPRINT-2 trial, gave a talk at the EASL meeting outlining the utility of using an interleukin (IL)-28B polymorphism as a baseline predictor of four- and eight-week response to triple-agent therapy. Dr. Poordad and colleagues from the SPRINT-2 and RESPOND-2 trials examined on SVR rates in patients with three different IL-28B polymorphisms: cysteine–cysteine, thymine–thymine and cysteine–thymine. They determined that the cysteine–cysteine polymorphism is associated most strongly with SVR response; patients with this polymorphism may be eligible for short-duration therapy.

Dr. Poordad’s team also found that lead-in response is a stronger predictor of SVR than any other single baseline characteristic, including IL-28B polymorphism. They concluded that because IL-28B polymorphism status and lead-in response “are powerful predictors of SVR,” the optimal approach may be to use both.

“Taken together, these data showed that the addition of boceprevir to peginterferon and ribavirin achieved significantly higher SVR rates in patients with chronic HCV genotype 1 compared with peginterferon and ribavirin alone, and that nearly half of all patients were eligible to receive a shorter duration of therapy,” Dr. Poordad said.

Telaprevir Trials

The REALIZE trial was a randomized, double-blind, placebo-controlled study of people who were previously treated unsuccessfully for HCV infection.

Subjects were randomized 2:2:1 into two telaprevir-based treatment arms—a “lead-in” arm and a “simultaneous-start” arm—and a control arm, which comprised 48 weeks of treatment with peginterferon-ribavirin alone. The lead-in arm included a four-week lead-in period of treatment with peginterferon-ribavirin followed by the addition of telaprevir for 12 weeks, then followed by 32 weeks of treatment with peginterferon-ribavirin alone. The simultaneous-start arm involved 12 weeks of triple-combination therapy, followed by 36 weeks of peginterferon-ribavirin alone.

Forty-eight percent (316 of 662) of the patients had advanced liver fibrosis or cirrhosis, and 89% (586 of 662) had a high HCV RNA load (≥800,000 IU/mL) at study entry.

The primary end point in all three groups was SVR. The results were analyzed based on three subgroups of patients: patients with undetectable levels of HCV RNA during at least 42 weeks of prior treatment that later became detectable (prior relapsers); patients who achieved at least a 2-log10 decrease in HCV RNA by week 12 of treatment but who did not achieve undetectable levels by week 24 (prior partial responders); and, those who did not achieve a 2-log10 decrease in HCV RNA by week 12 of treatment (prior null responders).

SVR rates for all patients in the telaprevir treatment arms were significantly greater compared with patients in the control group (Table; P<0.001). This held true for patients in the two telaprevir-containing arms combined, among which 86% (245 of 286) of the prior relapsers achieved SVR, 57% (55 of 97) of prior partial responders had an SVR and 31% (46 of 147) of the prior null responders had an SVR.

Table. SVR Rates in the REALIZE Trial
Treatment ArmPrior Relapsers (n=354)Prior Partial Responders (n=124)Prior Null Responders (n=184)
Lead-in with telaprevira88%d (124/141)54%d (26/48)33%d (25/75)
Simultaneous start with telaprevirb83%d (121/145)59%d (29/49)29%d (21/72)
Controlc (no telaprevir)24% (16/68)15% (4/27)5% (2/37)
a Four-week lead-in period of treatment with peginterferon-ribavirin, followed by the addition of telaprevir for 12 weeks, followed by 32 weeks of treatment with peginterferon-ribavirin alone
b Combination therapy with telaprevir and peginterferon-ribavirin for 12 weeks started simultaneously, followed by 36 weeks of peginterferon-ribavirin alone
c Forty-eight weeks of treatment with peginterferon-ribavirin alone
d P<0.001, compared with control
REALIZE, Re-treatment of Patients with Telaprevir-based Regimen to Optimize Outcomes; SVR, sustained virologic response

“We believe the data showed that an immediate start of a 12-week telaprevir-based regimen substantially improved viral cure rates in all three major subgroups of people who were not cured with currently available medicines,” said Robert Kauffman, MD, PhD, senior vice president and chief medical officer, Vertex Pharmaceuticals.

The most common AEs in the telaprevir studies were fatigue, pruritus, nausea, headache, rash and anemia. Anemia occurred in 36% of patients in the treatment lead-in arm, 30% of subjects in the simultaneous-start arm and 15% in the control arm; erythropoietin treatment was not allowed in the study. Rash was present in 36% of patients in the lead-in arm, 37% in the simultaneous-start arm and 19% of the control arm. Three percent of patients in the telaprevir-treatment arms discontinued all treatment because of anemia and 3% did so because of rash. (No P values were provided.)

Series Editor
Tarun Mullick, MD

Clinical Faculty
Rush-Copley Medical Center
Aurora, Illinois
Clinical Staff
Delnor Hospital
Geneva, Illinois
Provena Mercy Medical Center
Aurora, Illinois

Commentary by Dr. Mullick

For the past decade, treatment with pegylated interferon and ribavirin for hepatitis C virus (HCV) genotypes 2 and 3 was able to provide a sustained virologic response (SVR) of approximately 80% after 24 weeks of treatment. However, the more difficult to treat HCV genotype 1 not only requires 48 weeks of treatment with pegylated interferon and ribavirin, but also is associated with an SVR ranging from 40% to 50%.
The problem with pegylated interferon and ribavirin and prior therapies was that they do not target the virus directly in a way that effectively puts the virus in a dormant state. Until now, therapies for patients with HCV genotype 1 infection were limited in their efficacy.
With the arrival of two new HCV protease inhibitors, telaprevir and boceprevir, we now have drugs available that target the virus in a more direct and effective manner. In combination with pegylated interferon and ribavirin, the new protease inhibitors cut the duration of treatment to 24 weeks and achieve an SVR approaching 80%!
The potential for side effects exists for each of the new drugs, with rash and bone marrow–related issues among them. Overall, however, this is the largest breakthrough in hepatitis C treatment in a decade.
By the time other future therapies become available, these medications will likely have treated 80% of patients with HCV infection. These drugs have the potential to dramatically reduce the number of HCV patients who develop cirrhosis, liver cancer and who require liver transplant for this disease.

Retrospective analyses of IL-28B polymorphisms in patients treated with telaprevir also were presented at the EASL meeting. Data from the ADVANCE (A New Direction in HCV Care: A Study of Treatment-Naive Hepatitis C Patients with Telaprevir) trial, a Phase III study of treatment-naïve patients with HCV, indicated that the cysteine–cysteine variation of the IL-28B polymorphism is associated with the highest SVR rates, at 90% compared with 73% among patients with the thymine–thymine polymorphism and 71% among individuals with the cysteine–thymine polymorphism.

Retrospective analysis of data from REALIZE indicated that the cysteine–cysteine variant also is associated with the highest SVR rates, at 79% compared with 61% for the thymine–thymine polymorphism and 60% for the cysteine–thymine polymorphism.

Additionally, interim results from a Phase II study of treatment-naïve HCV patients with the combination of telaprevir, peginterferon-ribavirin and the polymerase inhibitor VX-222 (Vertex) also were presented at the meeting. Of patients who received a combination of the four agents, 90% had undetectable HCV RNA after 12 weeks. In another group of patients who received a combination of the four agents with a lower dose of VX-222, 83% showed undetectable levels of HCV RNA.

“Boceprevir and telaprevir will greatly improve our ability to eradicate hepatitis C from both treatment-naïve as well as treatment-experienced patients,” commented Donald M. Jensen, MD, professor of medicine and director of the Center for Liver Disease, University of Chicago Medical Center, who wrote an editorial accompanying the published results of RESPOND-2 and SPRINT-2 (N Engl J Med 2011;364:1272-1274). “However, this success will come at a cost—an increase in side effects and some increase in treatment complexity.”


Noninvasive liver tests may predict hepatitis C patient survival

Public release date: 14-Jun-2011

Contact: Alissa J. Cruz
American Gastroenterological Association

Non-invasive tests for liver fibrosis, such as liver stiffness measurement or the FibroTest, can predict survival of patients with chronic hepatitis C, according to a new study in Gastroenterology, the official journal of the American Gastroenterological Association (AGA) Institute.

"Liver stiffness measurement and/or the FibroTest could replace liver biopsy for the evaluation of hepatitis C, regardless of the stage of the disease," said Victor de Lédinghen, MD, PhD, of the Centre d' Investigation de la Fibrose Hépatique and lead author of this study. "Thus, these tools may help physicians assess prognosis early and discuss specific treatments."

Findings of this study are of major importance since liver stiffness, as a good predictive factor of survival, may help physicians evaluate the severity of liver disease earlier, decide with stronger arguments on a liver transplant or a portosystemic shunt (to bypass the liver), and evaluate more precisely the surgical risk of cirrhotic patients.

In chronic liver diseases, fibrosis assessment predicts liver-related complications and survival. In this study, doctors evaluated the five-year prognostic value of liver stiffness, non-invasive tests of liver fibrosis and liver biopsy to predict overall survival and survival without liver-related death in chronic hepatitis C.

A total of 1,457 patients with chronic hepatitis C were included. At five years, 77 patients died (39 liver-related deaths) and 16 patients had liver transplantation. Overall survival was 91.7 percent and survival without liver-related death was 94.4 percent. Survival was significantly decreased in patients diagnosed with severe fibrosis, no matter which non-invasive method was used.

All methods were able to predict shorter survival times; liver stiffness measurement and results of the FibroTest had higher predictive values. Doctors assessed fibrosis and — on the same day — liver stiffness, performed noninvasive tests of fibrosis (FibroTest, the aspartate aminotransferase to platelet ratio index, FIB-4), and analyzed liver biopsy samples.

"To our knowledge, this study is the first showing that liver stiffness has a prognostic value for overall survival and survival without liver-related death in patients with chronic hepatitis C virus infection," added Dr. Lédinghen. "The present study independently validated the prognostic value of the FibroTest and showed that liver stiffness and FibroTest can predict survival."


For more information on hepatitis, please read the AGA brochure "Understanding Hepatitis" at www.gastro.org/patient-center/digestive-conditions/hepatitis.

About the AGA Institute

The American Gastroenterological Association is the trusted voice of the GI community. Founded in 1897, the AGA has grown to include 17,000 members from around the globe who are involved in all aspects of the science, practice and advancement of gastroenterology. The AGA Institute administers the practice, research and educational programs of the organization. www.gastro.org.

About Gastroenterology

Gastroenterology, the official journal of the AGA Institute, is the most prominent scientific journal in the specialty and is in the top 1 percent of indexed medical journals internationally. The journal publishes clinical and basic science studies of all aspects of the digestive system, including the liver and pancreas, as well as nutrition. The journal is abstracted and indexed in Biological Abstracts, Current Awareness in Biological Sciences, Chemical Abstracts, Current Contents, Excerpta Medica, Index Medicus, Nutrition Abstracts and Science Citation Index. For more information, visit www.gastrojournal.org.


Vertex and Alios BioPharma Announce Exclusive Worldwide Licensing Agreement for Two Nucleotide Drug Candidates, Broadening Vertex's Efforts to Develop New Combinations of Medicines for Hepatitis C

June 13, 2011

-Vertex gains worldwide rights to two distinct nucleotide analogues, ALS-2200 and ALS-2158, that act on hepatitis C polymerase-
-Collaboration provides multiple opportunities to develop new "all-oral" combination regimens-

CAMBRIDGE, Mass., & SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)-- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) and Alios BioPharma, Inc. today announced an exclusive worldwide licensing agreement that will add two distinct nucleotide analogues to Vertex's hepatitis C portfolio. The compounds, which were discovered by Alios and are known as ALS-2200 and ALS-2158, have shown in in vitro studies to be potent inhibitors of the hepatitis C virus (HCV) polymerase, an enzyme essential for replication of the virus. The addition of these compounds provides Vertex with multiple opportunities to develop potential, new, all-oral combination regimens for chronic hepatitis C. Vertex expects ALS-2200 and ALS-2158 to enter clinical development later this year.

"We are excited to begin working with Vertex, as we believe that the Alios nucleotide analogues provide an important opportunity to improve patient care in hepatitis C," said Lawrence M. Blatt, Ph.D., Founder and Chief Executive Officer of Alios BioPharma. "For more than a decade, Vertex has been a leader in the development of new approaches for treating hepatitis C, and together we have the potential to create an all-oral, interferon-free, combination therapy that could improve the safety, efficacy and ease of administration for patients. We look forward to initiating clinical development later this year."

"The recent approval of INCIVEK was a milestone in hepatitis C care, and today's announcement underscores our long-term commitment to further improving the treatment of this disease with new combinations of medicines," said Peter Mueller, Ph.D., Chief Scientific Officer and Executive Vice President of Global Research and Development at Vertex. "Alios has discovered anti-HCV nucleotides that have the potential to be leading agents in hepatitis C. Based on impressive in vitro data, we look forward to evaluating ALS-2200 and ALS-2158 together and in combination with our approved and investigational hepatitis C medicines with the goal of creating a highly potent all-oral regimen in the years ahead."

About ALS-2200 and ALS-2158

ALS-2200 and ALS-2158, currently in preclinical development, are highly potent nucleotide analogues that appear in in vitro and non-clinical studies to have a high barrier to drug resistance and the potential to be dosed once-daily. Both compounds are designed to inhibit the replication of the hepatitis C virus by acting on the NS5B polymerase. Each compound has its own unique mechanism of action, which supports the potential for developing these compounds together as a dual nucleotide regimen and as part of combination therapy regimens with Vertex's other approved and investigational medicines for chronic hepatitis C, including INCIVEKTM (telaprevir), an FDA-approved hepatitis C protease inhibitor, and VX-222, an investigational hepatitis C non-nucleoside polymerase inhibitor. Data from in vitro studies showed that both ALS-2200 and ALS-2158 had a synergistic effect when combined together and with INCIVEK and VX-222. Additionally, in those in vitro studies, both compounds showed antiviral activity across all genotypes, or forms, of the hepatitis C virus, including genotypes more prevalent outside of the U.S. Pan-genotypic compounds for hepatitis C have the potential to be used across a broad range of people with hepatitis C worldwide.

As part of this agreement, Vertex gains worldwide rights to both compounds, further enabling the company to potentially expand development and commercialization efforts in hepatitis C to areas outside North America over the coming years. The agreement also includes a research program that will focus on the discovery of additional nucleotide analogues that act on the hepatitis C polymerase. Vertex will have the option to select compounds for development emerging from the research program.

Future Development Plans: Alios and Vertex plan to initiate clinical development of each compound in the fourth quarter of 2011, which is expected to include studies of the compounds in healthy volunteers followed by short-duration safety and viral kinetic studies in people with hepatitis C. The goal of the first clinical studies of these compounds is to generate data to enable the initiation of Phase 2 studies as early as the end of 2012. These Phase 2 studies are expected to evaluate multiple combination regimens of ALS-2200, ALS-2158, INCIVEK and VX-222. The combination studies would be designed to generate sustained viral response (SVR or viral cure) data. Additional details on the clinical development program for ALS-2200 and ALS-2158 will be provided later in 2011 upon initiation of the first clinical study.

Terms of the Transaction

As part of the agreement, Alios will receive a $60 million up-front payment from Vertex for the worldwide rights to ALS-2200 and ALS-2158. Vertex is responsible for development costs related to ALS-2200 and ALS-2158 and will also provide research funding to Alios. In addition, Alios would be eligible to receive research and development milestone payments up to $715 million if both compounds are approved. Vertex expects to pay approximately $35 million in development milestones in 2011. Alios is also eligible to receive up to $750 million in sales milestones on sales of all approved medicines under the collaboration. The agreement also includes tiered royalties on product sales.

Important Information About INCIVEKTM (telaprevir) tablets

INCIVEKTM (telaprevir) is a prescription medicine used with the medicines peginterferon alfa and ribavirin to treat chronic (lasting a long time) hepatitis C genotype 1 infection in adults with stable liver problems, who have not been treated before or who have failed previous treatment.

It is not known if INCIVEK is safe and effective in children under 18 years of age.


INCIVEK should always be taken in combination with peginterferon alfa and ribavirin. Ribavirin may cause birth defects or death of an unborn baby. Therefore, you should not take INCIVEK combination treatment if you are pregnant or may become pregnant, or if you are a man with a sexual partner who is pregnant.

INCIVEK and other medicines can affect each other and can also cause side effects that can be serious or life threatening. There are certain medicines you cannot take with INCIVEK combination treatment. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements.

INCIVEK can cause serious side effects including rash and anemia. The most common side effects of INCIVEK include itching, nausea, diarrhea, vomiting, anal or rectal problems, taste changes and tiredness. There are other possible side effects of INCIVEK, and side effects associated with peginterferon alfa and ribavirin also apply to INCIVEK combination treatment. Tell your healthcare provider about any side effect that bothers you or doesn't go away.

You are encouraged to report negative side effects of prescription drugs to the FDA at 1-800-FDA-1088 OR 1-800-332-1088 or www.fda.gov/medwatch. You may also report side effects to Vertex at 1-877-824-4281.

Please see full Prescribing Information for INCIVEK including the Medication Guide, available at www.INCIVEK.com.

About Hepatitis C

Hepatitis C is a serious liver disease caused by the hepatitis C virus, which is spread through direct contact with the blood of infected people and ultimately affects the liver.1 Chronic hepatitis C can lead to serious and life-threatening liver problems, including liver damage, cirrhosis, liver failure or liver cancer.1 Though many people with hepatitis C may not experience symptoms, others may have symptoms such as fatigue, fever, jaundice and abdominal pain.1

Unlike HIV and hepatitis B virus, chronic hepatitis C is curable.2 However, approximately 60 percent of people with genotype 1 chronic hepatitis C do not achieve SVR,3,4,5 or viral cure,6 after treatment with 48 weeks of pegylated-interferon and ribavirin alone. If treatment is not successful and a person does not achieve a viral cure, they remain at an increased risk for progressive liver disease.7,8

More than 170 million people worldwide are chronically infected with hepatitis C.6 In the United States, nearly 4 million people have chronic hepatitis C and 75 percent of them are unaware of their infection.9 Hepatitis C is four times more prevalent in the United States compared to HIV.9 Genotype 1 is the most common form of HCV in the United States, accounting for around 70 percent of cases.13 However, different forms are more common in other parts of the world. The majority of people with hepatitis C in the United States were born between 1946 and 1964, accounting for two of every three people with chronic hepatitis C.10 Hepatitis C is the leading cause of liver transplantations in the United States and is reported to contribute to 4,600 to 12,000 deaths annually.11,12 By 2029, total annual medical costs in the United States for people with hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion.9

About Vertex

Vertex creates new possibilities in medicine. Our team discovers, develops and commercializes innovative therapies so people with serious diseases can lead better lives. Vertex scientists and our collaborators are working on new medicines to cure or significantly advance the treatment of hepatitis C, cystic fibrosis, epilepsy and other life-threatening diseases.

Founded more than 20 years ago in Cambridge, MA, we now have ongoing worldwide research programs and sites in the U.S., U.K. and Canada.

For more information and to view Vertex's press releases, please visit www.vrtx.com.

About Alios BioPharma

Alios BioPharma is a biotechnology company located in South San Francisco, California, that is developing novel medicines aimed at the treatment of viral diseases. Alios has an innovative team of highly experienced scientists and clinical researchers who are developing direct acting antiviral agents against several human viral pathogens of public health importance including, Hepatotropic viruses, Respiratory viruses and other chronic, acute and emerging viral diseases. Additionally, Alios is developing molecular activators of an interferon induced, broad spectrum antiviral innate immune pathway called RNase-L. The overall goal for the Alios therapeutic platform is to maximize patient benefits in areas of high unmet medical need through optimization of potency, safety and tolerability.
INCIVEK™ is a trademark of Vertex Pharmaceuticals Incorporated.

Special Note Regarding Forward-Looking Statements

This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including statements regarding (i) Vertex broadening its efforts to develop new combinations of medicines for hepatitis C; (ii) multiple opportunities to develop new "all-oral" combination regimens; (iii) the expectation that clinical development of ALS-2200 and ALS-2158 will begin in 2011; (iv) the potential to create an all-oral, interferon-free, combination therapy that could improve the safety, efficacy and ease of administration for patients; (v) Vertex's long-term commitment to further improving the treatment of Hep C with new combinations of medicines; (vi) the anti-HCV nucleotides having the potential to be leading agents in hepatitis C; (vii) the goal of creating a highly potent all-oral regimen in the years ahead; (viii) the potential for development of these compounds together as a dual nucleotide regimen and as part of combination therapy regimens with INCIVEK (telaprevir) and VX-222; (ix) the potential to expand development and commercialization efforts in hepatitis C to areas outside North America over the coming years; (x) Alios' future research program and Vertex's option to select compounds that may emerge from the research program; (xi) all of the statements under the caption "Future Development Plans;" (xii) Vertex's responsibility for development and research funding; and (xiii) potential development and commercialization milestones and royalty payments. While the Company believes the forward-looking statements contained in this press release are accurate, there are a number of factors that could cause actual events or results to differ materially from those indicated by such forward-looking statements. Those risks and uncertainties include, among other things, that the outcomes for our planned clinical trials and studies may not be favorable, that there may be varying interpretations of data produced by one or more of our clinical trials, that the Company may not obtain the benefits it expects to obtain from this transaction for a variety of reasons including the possibilities that the Company may not be able to successfully develop combination therapies involving INCIVEK and/or VX-222 and the drug candidates that the Company is acquiring in this transaction; and that in vitro data regarding ALS-2200 and ALS-2158 may not be predictive of results that may be obtained from clinical trials, and the other risks listed under Risk Factors in Vertex's annual report and quarterly reports filed with the Securities and Exchange Commission and available through the Company's website at www.vrtx.com. The Company disclaims any obligation to update the information contained in this press release as new information becomes available.


1 Centers for Disease Control and Prevention. Hepatitis C Fact Sheet: CDC Viral Hepatitis. Available at: http://www.cdc.gov/hepatitis/HCV/PDFs/HepCGeneralFactSheet.pdf. Accessed March 21, 2011.
2 Pearlman BL and Traub N. Sustained Virologic Response to Antiviral Therapy for Chronic Hepatitis C Virus Infection: A Cure and So Much More. Clin Infect Dis. 2011 Apr;52(7):889-900.
3 Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965.
4 Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982.
5 McHutchison JG, Lawitz EJ, Shiffman ML, et al; IDEAL Study Team. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580-593.
6 Ghany MG, Strader DB, Thomas DL, Seeff, LB. Diagnosis, management and treatment of hepatitis C; An update. Hepatology. 2009;49 (4):1-40.
7 Morgan TR, Ghany MG, Kim HY, Snow KK, Lindsay K, Lok AS. Outcome of sustained virological responders and non-responders in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial. Hepatology. 2008;50(Suppl 4):357A (Abstract 115).
8 Veldt BJ, Heathcote J, Wedmeyer H. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Annals of Internal Medicine. 2007; 147: 677-684.
9 Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. Available at: http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx. Updated January 11, 2010. Accessed March 21, 2011.
10 Pyenson B, Fitch K, Iwasaki K. Consequences of hepatitis C virus (HCV): Costs of a baby boomer epidemic of liver disease. Available at: http://www.natap.org/2009/HCV/051809_01.htm. Updated May 2009. Accessed March 21, 2011. This report was commissioned by Vertex Pharmaceuticals, Inc.
11 Volk MI, Tocco R, Saini S, Lok, ASF. Public health impact of antiviral therapy for hepatitis C in the United States. Hepatology. 2009;50(6):1750-1755.
12 Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: A multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010;138:513-521.
13 Blatt LM, Mutchnick MG, Tong MJ, et al. Assessment of hepatitis C virus RNA and genotype from 6807 patients with chronic hepatitis in the United States. J Viral Hepat. 2000; 7:196-202.

Vertex Pharmaceuticals Incorporated

Michael Partridge, 617-444-6108
Lora Pike, 617-444-6755
Matthew Osborne, 617-444-6057
Zachry Barber, 617-444-6992
John Donovan, 650-635-5504
Chief Business Officer

Source: Vertex Pharmaceuticals Incorporated


Massive Opportunity Exists in Hepatitis C Market for Recently Approved Protease Inhibitors Victrelis and Incivek According to a New Report by BioTrends Research Group

In TreatmentTrends®: Hepatitis C, BioTrends surveyed 150 gastroenterologists, hepatologists and infectious disease specialists about their current treatment of HCV, perceptions of Roche’s Pegasys and Merck & Co’s PegIntron, and anticipated future changes in disease management with emphasis on the expected use of Victrelis and Incivek.

The vast majority of respondents reported a high unmet need for HCV treatment options and noted that a high proportion of both prior treatment failures and treatment-naïve patients were waiting for approval of the new protease inhibitors before initiating (or re-initiating) therapy. In fact, the survey respondents reported that the leading change in treatment patterns over the past year was the “warehousing” of patients (delaying treatment) in anticipation of the approval of new treatment options. Within six months, respondents estimate that approximately three-quarters of genotype 1 HCV patients will be treated with the triple regimen of a protease inhibitor, peg-interferon and ribavirin.

Pegasys and PegIntron will likely see a boost related to the warehoused patients being initiated on triple therapy regimens. However, physicians are divided about which peg-interferon they will likely choose for these combination regimens. About one-third of the respondents report that they will follow the clinical trial regimen (PegIntron/Victrelis or Pegasys/Incivek), another third will use the peg-interferons interchangeably with either protease inhibitor and the remaining third will stick with their preferred peg-interferon regardless of which protease inhibitor brand they select.

The most desired attributes in new agents for the treatment of HCV were all efficacy oriented, despite the fact that many patients discontinue HCV therapy due to poor tolerability. There were no significant differences in familiarity or interest ratings between Victrelis and Incivek, although the survey respondents predicted higher market share for Incivek in the first six months of launch. BioTrends will follow the market uptake of Victrelis and Incivek in its LaunchTrends series, which will pulse the market at one, three and six months post launch to assess trial and adoption, promotional efforts and obstacles to growth for both brands.

About BioTrends Research Group, LLC

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About Decision Resources, Inc.

Decision Resources, Inc. is a cohesive portfolio of companies that offers best-in-class, high-value information and insights on important sectors of the healthcare industry. Clients rely on this analysis and data to make informed decisions. Please visit Decision Resources, Inc. at www.DecisionResourcesInc.com.

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Decision Resources, Inc.
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